Application Of Control Engineering Principles To The Calculation Of Pharmaceutical Drug Doses
Today, I was asked by an eminent cardiologist to give my opinion on this scientific paper in the Journal of the American Heart Association, which was entitled Personalized Antihypertensive Treatment Optimization With Smartphone‐Enabled Remote Precision Dosing of Amlodipine During the COVID‐19 Pandemic (PERSONAL‐CovidBP Trial).
This was the background to the study.
The objective of the PERSONAL‐CovidBP (Personalised Electronic Record Supported Optimisation When Alone for Patients With Hypertension: Pilot Study for Remote Medical Management of Hypertension During the COVID‐19 Pandemic) trial was to assess the efficacy and safety of smartphone‐enabled remote precision dosing of amlodipine to control blood pressure (BP) in participants with primary hypertension during the COVID‐19 pandemic.
These were the methods and the results.
This was an open‐label, remote, dose titration trial using daily home self‐monitoring of BP, drug dose, and side effects with linked smartphone app and telemonitoring. Participants aged ≥18 years with uncontrolled hypertension (5–7 day baseline mean ≥135 mm Hg systolic BP or ≥85 mm Hg diastolic BP) received personalized amlodipine dose titration using novel (1, 2, 3, 4, 6, 7, 8, 9 mg) and standard (5 and 10 mg) doses daily over 14 weeks. The primary outcome of the trial was mean change in systolic BP from baseline to end of treatment. A total of 205 participants were enrolled and mean BP fell from 142/87 (systolic BP/diastolic BP) to 131/81 mm Hg (a reduction of 11 (95% CI, 10–12)/7 (95% CI, 6–7) mm Hg, P<0.001). The majority of participants achieved BP control on novel doses (84%); of those participants, 35% were controlled by 1 mg daily. The majority (88%) controlled on novel doses had no peripheral edema. Adherence to BP recording and reported adherence to medication was 84% and 94%, respectively. Patient retention was 96% (196/205). Treatment was well tolerated with no withdrawals from adverse events.
These were the conclusions.
Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App‐assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long‐term care.
About Myself
I am a Graduate Control Engineer, who graduated from the University of Liverpool in 1968.
I then worked at ICI in Runcorn for eighteen months, before moving to ICI Plastics Division, because of the untimely death of my father-in-law.
One of my tasks at Welwyn, was to look at control algorithms for chemical plants. For this I often used a PACE 231-R analogue computer.
Note.
- These computers could solve up to a hundred simultaneous differential equations at one time.
- They were programmed by wiring the various amplifiers and potentiometers together to simulate the equations.
- There were only a few transistors in these powerful machines, as all electronics were thermionic valves.
- Two of these machines wired together, were used to calculate the trajectories of the Apollo missions.
They were the unsung heroes of bringing Jim Lovell and Apollo 13 home safely.
Determining Control Algorithms
In a typical problem, I would model the a section of a chemical plant and the control system around it.
This would then lead to recommendations, as to the design and operation of the plant, so that it performed as required.
It could be argued that the body of an animal, is a very complicated integrated chemical plant, with a sophisticated control system.
For instance, if sensors around the body, say you are slightly low on fluids, your brain determines you should have a drink.
Many control loops on a chemical plant are controlled by proportional–integral–derivative controllers, which are commonly known as three-term controllers.
This is the first two paragraphs of the Wikipedia entry for three-term controllers.
A proportional–integral–derivative controller (PID controller or three-term controller) is a control loop mechanism employing feedback that is widely used in industrial control systems and a variety of other applications requiring continuously modulated control. A PID controller continuously calculates an error value
PID systems automatically apply accurate and responsive correction to a control function. An everyday example is the cruise control on a car, where ascending a hill would lower speed if constant engine power were applied. The controller’s PID algorithm restores the measured speed to the desired speed with minimal delay and overshoot by increasing the power output of the engine in a controlled manner.
I wouldn’t be surprised that the app in the smartphone used in the PERSONAL‐CovidBP Trial contained a form of three-term controller.
These are some points about three-term control algorithms.
Changing Of External Factors
One that was the villain in a problem, I dealt with, also affects my body – the weather.
I was asked to look at the problem of a chemical reaction, that overheated in hot weather. But the plant operators solved it by better insulation and ventilation of the plant and the standard three-term controller adjusted itself automatically to the new conditions.
After my stroke, I am on Warfarin for life. I test my own INR with a Roche meter and I have noticed that atmospheric pressure affects my INR. I change my deose accordingly, using a simple algorithm, of my own design.
The More You Test The More Precise The Control
If you take the cruise control example used by Wikipedia, speed is monitored continuously, as I hope, it would be if you were driving yourself.
But obviously, in many systems, where you are using an input with discrete values to control a system, you can’t be as precise as the data you collect.
When my son was dying from pancreatic cancer, he was fitted with a morphine pump, that he could adjust himself to dull the immense pain he was enduring.
- His nerves and his brain ascertained the pain level.
- He then adjusted the morphine level.
- He could get very precise control of his pain, because he was measuring it continuously.
But he was only using simple one-term control (proportional).
Derivative Control Can Be Difficult To Get Right And Can Even Go Unstable
Derivative control is mainly to stop overshoot, but sometimes you will find that it can go unstable, so two-term(proportional+integral) controllers will be used.
How I Control My INR
As I said earlier, I am on Warfarin for life and test my INR with a Roche meter.
The NHS typically tests patients about once every six weeks, which in my opinion as a Control Engineer is too infrequent.
I usually test myself a couple of times a week.
But every so often, I evaluate what daily dose gives me an equilibrium INR level of 2.5.
For the last three years, I have found a dose of 3.75 mg keeps me more or less on 2.5.
- As Warfarin comes in 1, 3, 5 and 10 mg. tablets, I alternate 3.5 and 4 mg.
- Warfarin tablets are easily cut in half using a sharp knife.
- I record INR and dose in a spreadsheet.
I have been doing this now for over ten years.
Is This A Unique Property Of Warfarin?
In this time, I have had five medical procedures, where surgeons were worried, that as I was on Warfarin, I might bleed too much.
For the first, which was to remove a lump from my mouth, the private surgeon wanted to charge extra for an anaesthetist. In the end, I asked what INR he wanted and he said 2.1 should be OK!
- So I reduced the Warfarin level and tested every day.
- I judged it correctly and had an INR of 2.1 on the day of the operation.
- The operation went incredibly well and I went home on public transport.
- The lump turned out to be benign.
- I’ve not had another lump.
After the operation, I increased the Warfarin level and tested every day, until it regained a level of 2.5.
On analysing my doses through the date of the operation, I found that the total amount of Warfarin, I didn’t take to reduce my INR to 2.1, was the same as I took to bring it back up again to 2.5.
Is this a unique property of Warfarin?
Since then I’ve had two cataract operations performed in a private hospital, where the NHS paid. Interestingly, they wouldn’t trust my own INR readings, so I had to get my GP to take the measurement.
I’ve also had gallstones removed by endoscopy at the local Homerton NHS hospital.
- For cases like mine, the hospital hire in a surgeon from the posh Wellington private hospital for one day a week, who brings the specialist tools needed.
- I wrote about this in Goodbye To My Gallstones.
- As it was a more serious procedure, I reduced my INR to a requested 1.0.
Interestingly, I still have my gall bladder, but the surgeon put it on notice to behave.
Conclusion
I would totally agree with the conclusion given in the PERSONAL‐CovidBP Trial.
Personalized dose titration with amlodipine was safe, well tolerated, and efficacious in treating primary hypertension. The majority of participants achieved BP control on novel doses, and with personalization of dose there were no trial discontinuations due to drug intolerance. App‐assisted remote clinician dose titration may better balance BP control and adverse effects and help optimize long‐term care.
I would add some conclusions of my own.
- The app used in the PERSONAL‐CovidBP Trial, seems to have had a good algorithm.
- I suspect the app could also be Internet-based.
These are some general conclusions.
- If you are on Warfarin and have access to a Roche meter, it is possible to lower your INR to the value required by a surgeon for an operation or a procedure.
- Since starting to take Warfarin, I have had four operations or procedures, where others would have had anaesthetic or a sedative.
- In those four operations, I was able to go home on public transport. If I still drove a car, I could have driven home afterwards.
- Private hospitals like to use an anesthetist, as it pumps up the bill.
- Avoiding anaesthesia must save hospitals money.
Well designed apps, based on Control Engineering principles, that help the patient take the best dose of a drug will become more common.
The Great Cadaver Shortage: Inside Doctors’ Latest Crisis
The title of this post, is the same as that of this article in The Times.
This is the sub-heading.
Faced with a dwindling supply of fresh bodies to train on, British medical schools are having to turn to America’s low-regulation ‘tissue trade’. Would you donate yours, asks Jenny Kleeman
My late wife, C; left her body to medical science and I may well choose to do the same with my body.
She left her body to St. George’s Medical School, mainly because one of her friend’s mother had done the same and there had been no problems.
Looking back on the nearly twenty years since she died, I remember a few months after her death, there was a multi-faith joint Memorial Service in Southwark Cathedral for all those who’d donated their bodies, in the previous year.
None of my family were or are religious, but I’m sure the service helped our grieving, as it was a very moving and inclusive service, that was the Church of England at its best, with assistance from other faiths.
Perhaps if donation were to be linked to support for the bereaved and perhaps a Memorial Service, this might increase the level of donations.
What sort of affect would it create in a city like Liverpool, if the yearly service alternated around the major places of worship in the city and was well-covered on local media?
Why Don’t Whales Get Cancer? Cracking One Of Medicine’s Greatest Mysteries
The title of this post, is the same as that of this article on The Guardian.
This is the sub-heading.
Understanding why some animals are more susceptible to the disease could lead to improved screening for humans
These are the first three paragraphs
Scientists are homing in on one of medicine’s most baffling mysteries: why some species avoid getting cancers while others are plagued by tumours that shorten their lives.
Whales tend to have low rates of cancer but it is the leading cause of death for dogs and cats. Foxes and leopards are susceptible while sheep and antelopes are not. Bats are also relatively well protected against cancer but not mice or rats. In humans, cancer is a leading cause of death that kills around 10 million people a year.
Even more puzzling is the fact that many huge creatures, including whales and elephants, generally avoid cancer when, instead, they should be at special risk because they possess vast numbers of cells, each of which could trigger a tumour.
The article is definitely a must-read.
A Funny Wet Week
I’ve had a funny few days as regards my health.
Tursday morning, my INR was 2.1.
On Friday night, I wasn’t sleeping very well and got up at three on Saturday morning. But after a couple of mugs of tea, I was feeling a lot better.
I had my usual Saturday morning breakfast in Leon on Moorgate, but I did get slightly confused with my shopping in Marks & Spencer. I put this down to my eyesight having an off day. Is that normal after two cataract operations?
I slept better on Saturday night! But was this because I went to bed before instead of after Match of the Day and then watched it on Sunday morning.
On Sunday morning, I went out to do a bit of shopping, but it was really just to get out and then it was walking in the pouring rain.
Monday was a quiet day, after breakfast in Leon on Moorgate, I wrote for most of the day. My INR was a bit low at 2.2.
Tuesday morning, it was a repeat of Friday night and I got up at four and had a couple of mugs of tea. It was another breakfast in Leon on Moorgate and a visit to M & S. After I returned, I wrote for most of the day, as it was too wet to go outside.
In the afternoon, I started to get a bit unsteady on my feet and even thought about calling 999. But after two mugs of tea and a can of Adnams, I regained my balance and never fell. My blood pressure was fine and the only unusual thing, was that my left food was quite red. But it does this sometimes.
Wednesday was uneventful and I had lunch with a friend at Cote in Sloane Square.
Today, Thursday my INR is down to 2.
I feel OK, but it does seem, that for some reason my INR has tended to slump during the week.
I just wonder if my leaky skin, just lets water out, which surely must lower the INR.
Does my foot go red, as the red blood corpuscles are too big to get through my skin?
Binge Drinking And Obesity Behind Bowel Cancer Surge In Under-50s
The title of this post, is the same as that of this article in The Times.
This is the sub-heading.
Deaths this year are set to be a third higher than in 2018 with biggest increase among young women
These three paragraphs introduce the article.
Obesity and binge drinking are causing a surge in bowel cancer among young British adults, research shows.
Deaths in those aged under 50 are set to be about a third higher this year than in 2018, with the highest increase in young women.
Bowel cancer is the third most common cancer in the UK, after breast and prostate cancers, and there are 43,000 new cases and 16,000 deaths a year. More than nine in ten cases are in those over 50, but the disease is increasingly being diagnosed in those under 50, in whom it is more likely to be aggressive and deadly.
I am coeliac and whenever, I see some illness that is more common in females, I wonder, if this is down to the fact, that female coeliacs are more common than males. This page on the NHS web site flags it up with this sentence.
Reported cases of coeliac disease are higher in women than men.
This could be because coeliac disease can cause complications in pregnancy, so more women get tested.
The NHS web site also links coeliacs with bowel cancer, but it does say this.
Once you’ve been following a gluten-free diet for some time, your risk of developing these types of cancer is the same as that of the general population.
My son was an undiagnosed coeliac, who worked in the music business. He lived on a diet of ciggies, cannabis and Subways and contracted pancreatic cancer, which killed him at just 37.
He should have got himself tested, as the NHS says, that if you have a first degree relative (Me!), who has coeliac disease, then you should get tested.
So if you think, you have a problem with gluten, get yourself tested!
If not for yourself for your family!
I am surprised that the Italian lead researcher doesn’t mention coeliac disease as Italy has lots of it! All that pasta and pizza!
The Cure For White Coat Hypertension
At one of my previous GP practices the two excellent nurses had banned my GP from taking blood pressure as she always raised the patient’s blood pressure, by the way she took the pressure.
This page on a blog at the London Cadiovascular Clinic is entitled White Coat Hypertension, gives this definition.
White coat syndrome, also known as white coat hypertension is a phenomenon in which your blood pressure is artificially raised due to the stress of being in a clinic, hospital, or even just taking your own blood pressure. This usually happens due to the stress and anxiety associated with having medical investigations done. Your reading will be higher than it would be if you measured it at home.
A week ago, I had a message from my GP practice to come in and measure my blood pressure in their machine in the waiting room.
So I went in and took my blood pressure about an hour ago.
I just put my hand in the hole at the front, shook hands with the machine, pressed the green button on top and it inflated a glove around my hand and lower arm to take the pressure.
Ears Are A Black Body
When I worked for ICI in Runcorn in 1968, one of my colleagues; John Baxendale developed or acquired one of the first remote infra-red thermometers.
ICI needed one for taking the temperature of hot vessels , pipes and reactors on chemical plants and in laboratories. John’s thermometer solved the problem, by measuring the black body radiation of the object.
John found that to calibrate his instrument he could point it at a colleague’s ear. As the ears emit black body radiation, the device should have read 36.9°C, as it generally did.
These so-called tympanic thermometers are now in regular use and cost about twenty pounds.
John is one of those people that has stuck in my mind from all those years in the past. He was a surfer and probably the only one, I’ve ever met in my life. I remember some weekends, he used to take his Morris Minor Traveller all the way to the North of Scotland to go surfing. Visiting that area has been on my bucket list for years. The closest I got, was to fly in my Cessna 340A to the Orkneys.
The Weather And My INR
I measure my own INR and adjust my levels of Warfarin accordingly.
I typically take 4 mg of Warfarin one say and 3.5 mg the next, as this average dose of 3.75 mg, seems to keep my INR around the required 2.5.
Recent readings have been as follows.
- 18th December – 2.5
- 21st December – 2.5
- 25th December – 2.7
- 28th December – 1.9
Note.
- I test on Mondays and Thursdays.
- Today’s test was a bit low at 1.9.
- I should also say my left humerus was uncomfortable. Was it because bone was unhappy being in a dry body?
Today I took 5 mg of Warfarin to kick the INR the right way. I shall also test my INR tomorrow, just to be sure.
So why did my IRN drop by an unusual amount between Monday and Thursday?
We have just had storm Gerrit (Who thinks up these names? Donald, Nigel or Vladimir would be better, as they’re Low-life!)
So does the the low pressure suck the water out of my body, thus lowering the INR? And bring pain to my injured arm?
Wood Burning At Home
The title of this post, is the same as that of the title on the home page of this web site.
I actually accessed the page as it appeared as an advert on something I was looking at on the Internet.
This is the sub-heading.
How do you feel about open fires, wood burners and even wood smoke?
These four paragraphs make up the home page.
It has long been known that the small particles released by solid fuel burning can stay in the air and even travel long distances. These small particles, when inhaled, can increase your risk of stroke, asthma, lung cancer, heart disease and dementia.
It is estimated that around 4,000 premature deaths occur each year in London due to long-term exposure to air pollution, of which about 284 are attributable to domestic wood burning. Every one of those 284 deaths is completely avoidable.
Domestic wood burning has a health and economic cost of about £187 million per year in London. That’s a cost of £24 for every London resident, whether you burn solid fuels or not.
The most effective way of reducing pollution and protecting everyone’s health is simply to avoid burning any wood, coal, or other solid fuels at home.
As I don’t have naked flames at all in my house, this doesn’t apply to me.
When I helped to fund two guys, who were developing a metered dose inhaler for asthma drugs, I did my due diligence before I invested.
I found some research, that said that naked flames and the oxides of nitrogen they produce, were one of the main causes of asthma.
So I avoid them and don’t do barbecues, bonfires, gas cookers or gas fires.
Incidentally, the two guys did develop the metered dose inhaler for asthma drugs and it is now prescribed as Respimat. It is totally mechanical, with no compressed gases or batteries.
‘Breakthrough’ Blood Test For Sepsis To Save Lives
The title of this post, is the same as that of this article in the Sunday Times.
This is the sub-heading.
If the trial is a success it could allow speedy diagnosis for a condition that kills 48,000 people a year
These two paragraphs introduce the story.
A blood test is being trialled that can rapidly detect whether a patient has sepsis, in what could be a breakthrough for a condition that is notoriously difficult to diagnose.
Sepsis, which occurs when the immune system overreacts to an infection, kills about 48,000 people each year in the UK. More people die of it annually than of breast, prostate and bowel cancer put together. In severe cases, it can kill within hours.
A friend had sepsis and it nearly killed her. A test like this would probably have shortened her time in hospital.
I am coeliac and also a mathematical modeller and statistician.
- If you are coeliac and stick to your gluten-free diet, which now includes delicious real ale, you are 25 % less likely to suffer from cancer than the general population, according to research at Nottingham University.
- The reverse of this means that an undiagnosed coeliac living a rock ‘n’ roll lifestyle with lots of smoking, cannabis and a diet of gluten-rich junk food, you will have a higher chance of contracting cancer. Just as my undiagnosed coeliac son did, who died of pancreatic cancer at just 37.
- Coeliac testing was difficult until around 1960, when a method using endoscopy was developed. Then in the 1990s, a general test using blood was developed.
I have analysed NHS cancer statistics and there is a step-reduction in cancer rate for those born after 1960 and 1990.
A simple blood test for coeliac disease has found a lot more coeliacs and saved a lot of lives.
My analysis is shown in detail in Hospital Pioneers Cancer Service For Over 70s That Saves Lives And Money.
For that reason, I believe that this new sepsis test could also save a lot of lives.
Coeliac Disease And Risk Of Sepsis
The title of this section, is the same as that of this paper on the British Medical Journal.
This is the conclusion of the paper.
This study showed a modestly increased risk of sepsis in patients with coeliac disease with the highest risk for pneumococcal sepsis. This risk increase was limited to those with coeliac disease diagnosed in adulthood. Potential explanations include hyposplenism, increased mucosal permeability and an altered composition of the intestinal glycocalyx in individuals with coeliac disease.
Perhaps anyone, who goes into hospital, should also be tested for coeliac disease?
Nitrous Oxide–Induced Vitamin B12 Deficiency
The title of this post, is the same as that of this peer-reviewed paper on the National Library of Medicine.
This is the abstract.
Nitrous oxide is a gas that is odorless, colorless, and has a sweet taste at room temperature. Nitrous oxide has several uses, including in surgery and dentistry (referred to as “laughing gas”), in automotive racing, and in aerosol spray propellants. The aerosol spray propellants that typically use nitrous oxide are whipped cream canisters and cooking sprays. Unfortunately, these over-the-counter household items are a source of nitrous oxide that can be used for recreational use. The most popular is the use of industrial-grade canisters having the slang term “whippets.” The nitrous oxide can be extracted by pushing the nozzle down slightly to the side and catching the released gas with a balloon. The contents of the balloon can then be directly inhaled, giving an instant feeling of euphoria. This is not a benign means to achieve a euphoric state but can cause severe nitrous oxide–induced B12 deficiency, which is presented in this case report.
An estimated 800,000 young adults abuse inhalants every year, and almost 11% of high school seniors report using inhalants at least once in their lifetime . Heavy inhalant abuse can result in a variety of side effects, including cardiac arrhythmias, hypoxia, metabolic acidosis, and neurologic deficits. Of all inhalants, nitrous oxide is particularly toxic due to its conversion of the active monovalent form of vitamin B12 to its inactive bivalent form. We present a case of subacute combined degeneration of the spinal cord due to nitrous oxide–induced vitamin B12 deficiency.
Basically, don’t inhale nitrous oxide, unless it’s being administered by a anaesthetist or a dentist.
Interestingly, because I was an undiagnosed coeliac my vitamin B12 was running on empty for much of the first fifty years of my life.
As my B12 was so low and didn’t really respond to regular injections, I was sent off to Addenbrooke’s, where they quickly diagnosed coeliac disease.
I wonder what would happen to an undiagnosed coeliac, who was low in B12, who got addicted to nitrous oxide.
The abstract implies that inhalants can cause cardiac arrhythmias, which has this Wikipedia entry, where this section talks about atrial fibrillation.
Arrhythmia affects millions of people. In Europe and North America, as of 2014, atrial fibrillation affects about 2% to 3% of the population. Atrial fibrillation and atrial flutter resulted in 112,000 deaths in 2013, up from 29,000 in 1990. However, in most recent cases concerning the SARS-CoV‑2 pandemic, cardiac arrhythmias are commonly developed and associated with high morbidity and mortality among patients hospitalized with the COVID-19 infection, due to the infection’s ability to cause myocardial injury. Sudden cardiac death is the cause of about half of deaths due to cardiovascular disease and about 15% of all deaths globally. About 80% of sudden cardiac death is the result of ventricular arrhythmias. Arrhythmias may occur at any age but are more common among older people. Arrhythmias may also occur in children; however, the normal range for the heart rate varies with age.
Doctors tell me, that my stroke was caused by atrial fibrillation.
The Anonymous Widower 